1-Imidocarbonyl-2-(1H)-pyridones and method of preparing same

ABSTRACT

In addition to cyanation of the nucleophile, the reaction of 2oxo-1(2H)-pryidinecarbonitrile and derivatives thereof with a nucleophile of formula QM from which an anion may be generated results in addition of the nucleophile to the carbonitrile function to form an imidocarbonyl derivative of the formula   WHEREIN EACH R may be the same or different and may be hydrogen, lower alkyl or lower alkenyl of up to 12 carbon atoms, hydroxyl, lower alkoxy of up to 12 carbon atoms, nitro, cyano, halogen, carboxy, amido, mercapto, aliphatic or aromatic acyl radicals of up to 20 carbon atoms, a phenyl radical substituted by one of the foregoing substituents, phenyl or aryloxy of up to 10 carbon atoms, Q may be alkyl, alkoxy, thioalkyl, aryl, aryloxy, arylthio, amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, or a basic nitrogen containing heterocyclic radical attached to C through the nitrogen atom, and M may be H, alkali metal, alkaline earth metal, Tl, divalent Cd, MgBr, MgQ or CaQ. The imidocarbonyl compounds absorb ultraviolet light and are useful as sun screen agents.

United States atet [191 Parker et al.

[ Mar. 25, 1975 1 l-lMIDOCARBONYL-2-(1H)-PYRIDONES AND METHOD OF PREPARING SAME [73] Assignee: E. R. Squibb & Sons, Inc., New

York, NY.

[22] Filed: May 28, 1971 [21] Appl. No.: 148,208

[52] US. Cl. 260/247.2 A, 260/242, 260/270 R, 260/287 R, 260/293.69, 260/294.8 G,

[51] Int. Cl C07d 87/42 [58] Field of Search.. 260/247.2 A, 294.8 G, 297 Z, 260/270 R, 293.69, 287 R, 296 R, 242

Primary Examiner-Donald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Burton Rodney [57] ABSTRACT In addition to cyanation of the nucleophile, the reaction of 2-oxo-1(2H)-pryidinecarbonitrile and derivatives thereof with a nucleophile of formula QM from which an anion may be generated results in addition of the nucleophile to the carbonitrile function to form an imidocarbonyl derivatiye of the formula wherein each R may be the same or different and may be hydrogen, lower alkyl or lower alkenyl of up to 12 carbon atoms, hydroxyl, lower alkoxy of up to 12 carbon atoms, nitro, cyano, halogen, carboxy, amido. mercapto, aliphatic or aromatic acyl radicals of up to 20 carbon atoms, a phenyl radical substituted by one of the foregoing substituents, phenyl or aryloxy of up to 10 carbon atoms, Q may be alkyl, alkoxy, thioalkyl, aryl, aryloxy, arylthio, amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, or a basic nitrogen containing heterocyclic radical attached to C through the nitrogen atom, and M may be H, alkali metal, alkaline earth metal, Tl, divalent Cd, MgBr, MgQ or CaQ. The imidocarbonyl compounds absorb ultraviolet light and are useful as sun screen agents.

3 Claims, No Drawings METHOD OFPREPARING SAME OBJECTS OF THE INVENTION It is an object of the present invention to provide new compounds which absorb ultraviolet light and which are useful as sun screen agents. Another object is to provide a method for the preparation of these compounds. These and other objects of the present invention will be apparent from the following description.

BACKGROUND OF THE INVENTION about 0C. The compound of formula II is extracted from the aqueous medium by means of a waterimmiscible organic solvent, such as an ester, e.g., ethyl acetate; an ether, e.g., ethyl ether; a halogenated alkane, e.g., chloroform; or an aromatic solvent, e.g., benzene, toluene or Xylene.

The compound of formula Il may also be prepared by reacting an alkali metal salt of a Z-pyridone compound of formula III with a cyanogen halide. This reaction takes place in a polar solvent at lowered temperatures Suitable solvents are amides, e.g., dimethylformamide or dimethylacetamide; or ethers, e.g., bis(2- metho'xyethyU-ether. Suitable temperatures are from about l0C to about 10C, preferably at about 0C.

The alkali metal salt of the 2-pyridone compound of formula III may be obtained by reacting a compound of formula III with an alkali metal hydroxide, e.g., LiOH, NaOH or KOH; an alkali metal hydride, e.g., LiH, NaH or KH; an alkali metal amide, e.g., LiNH NaNH or KNH or an alkyl organo-alkali metal compound, e.g., Li-butyl, Na-butyl or K-butyl.

The cyanogen halide employed to convert the alkali metal salt of the compound of formula III to the corresponding compound of formula II is preferably cyanogen bromide or cyanogen chloride.

Nitrite salt 1) alkali cyanogen halide g p o octadecanol, 2 methyl-l-propanol, isoamylalcohol,

2-methyl-l-butanol, benzyl alcohol, cyclohexylcar- It has now been found that the reaction of a 2-oxo- 1 1 ethylene g|yo1 and "methylene glycol. l(2H)-pyridinecarbonitrile compound of formula II with a nucleophilic compound produces an imidocar- 5 Secondary alcohols Such as alkanols cycloalk' bony] compound in addition to cyanating the nucleophile. The imidocarbonyl compound is formed by addition of the nucleophile to the carbonitrile function.

The reaction between the compound of formula II w l v I a and the nucleophilic compound may be illustrated by C. Tertiary alcohols, such as alkanols, cycloalkanols propanol, 2-methyl-2-propanol, 3-methyl-2- butanol, Z-pentanol, 3-pentanol, 3-hexanol, benzhydrol, cyclohexanol and dicyclohexylcarbinol.

the following equation: and aryl-substituted alkanols, e.g., t-butanol, t-

fi QM R N O I II III IV rt. 652507526925 R; aagsmsr fauna "*arriyr masher; 23-aimethyi-2 5mz55ijiiibne'n iand the nucleophile of formula QM takes place in the carbinol and tricyclohexylcarbinol. presence of easily volatilized inert solvents, that is, 501- 25 D. Mixed alcohols having primary and secondary alvents which have a boiling point not over about l00C cohol groups, e.g., propylene glycol, glycerol, at atmospheric pressure. The choice of solvents de- ,Bmethylglycerol, glucose, fructose, apiose, manpends essentially upon the solubilities of the reactants/ nose, mannitol, galactose and acrose. The reaction may take place at temperatures in the: II. Thiols containing from 1 to 20 carbon atoms corrange of about 0C to about the boiling point of the solresponding to the foregoing alcohols. The thiols, or vent. Examples of suitable solvents are ethers, e.g., mercaptans,are prepared conveniently by heating alkyl ethyl ether or dioxane, aromatic solvents, e.g., benhalides with sodium hydrosulfide. zene, toluene or xylene, aliphatic solvents, e.g., hexane III. Ammonia and organic amines containing from 1 anols and aryI-substituted alkanols, e.g., 2-

or heptane, halogenated solvents, e.g., chloroform or: lto 20 carbon atoms, and alkali and alkaline earth metal methylene chloride, and ketones, e.g., acetone or iderivatives thereof.

methyl ethyl ketone. A. Primary alkylamines, cycloalkylamines, arylsub- The reaction mixture is stirred for several minutes to; stituted alkylamines, and aromatic amines, e.g., an hour or more, typically for from about minutes methylamine, ethylamine, n-propylamine, isoto about 2 hours. The solvent is then removed under propylamine, n-butylamine, isobutylamine, t-

redu cedpres sure inure residue purified b y thin-layer 4O butylamine, n-amylamine, n-hexylamine, nchromatography on silica gel. A uv absorbing band is octylamine, Z-aminooctane, 2-ethyl-lcollected and washed from the silica gel. Removal of aminohexane, n-decylamine, laurylamine, cyclothe wash liquor gives the desired product of formula hexylamine, benzylamine, a-phenylethylamine, IV. ,B-phenylethylamine, aniline and a-aminopyridine.

The nucleophilic compound QM of formula Ill may B. Secondary amines such as dialkylamines, arylsubbe any compound from which an anion may be generstituted alkylamines, dicyclohexylamines and diarated, usually by means of a strong base. As typical nuylamines, and N-heterocyclic amines, e.g., dimethcleophilic compounds there may be mentioned alcoylamine, diethylamine, di-n-propylamine, diisoprohols, thiols, amines, ammonia, phenols, thiophenols, 5O pylamine, ethyl-secbutylamine, diphenylamine, Grignard reagents and malonic esters. Thus, the nubenzylaniline, N-methylaniline, N-ethylaniline, N-

cleophilic compound may have the formula QM phenylbenzylamine, N-methylbenzylamine, diphewherein Q may be alkyl, alkoxy, thioalkyl, aryl, arylnylamine, dicyclohexylamine, morpholine, piperi oxy, arylthio, amino, monoalkylamino, dialkylamino, dine, pyrrolidine, pyrrole, pyrrolidine, pyrazole, monoarylamino, diarylamino, or a basic nitrogen conimidazole, benzopyrrole, skatole, 2-methylindole, taining heterocyclic radical attached to M through the Z-phenylindole, l,2,3,4-tetrahydroquinoline, nitrogen atom, and wherein M may be H, alkali metal, decahydroquinoline and carbazole. MgBr, Tl, MgQ or CaQ. Reaction of a compound of IV. Phenols such as phenol and substituted phenols formula II with a nucleophile of formula QM forms an containing from 6 to 12 carbon atoms, such as o-cresol, imidocarbonyl compound of formula IV. m-cresol, p-cresol, o-chlorophenol, m-chlorophenol, Specific examples of such nucleophiles are the folp-chlorophenol, p-bromophenol, 2,4,6- lowing: trichlorophenol, 2,4,6-trifluorophenol, o-nitrophenol,

I. Alcohols containing from I to 20 carbon atoms m-nitrophenol, p-nitrophenol, 2,4-dinitrophenol, guai- A. Primary alcohols such as alkanols, cycloalkanols, acol, saligenin, carvacrol, thymol, o-hydroxydiphenyl,

and aryI-substituted alkanols, e.g., methanol, ethap-hydroxydiphenyl, o-cyclohexylphenol, pnol, n-propanol, n-butanol, n-pentanol, n-hexanol, cyclohexylphenol, catechol, resorcinol, hydroquinone, n-heptanol, n-octanol, n-nonanol, n-decanol, npyrogallol and phloroglucinol.

dodccanol, n-tetradecanol, n-hexadecanol, n- V. Thiophenols include thiophenol and substituted thiophenols containing from 6 to 12 carbon atoms corresponding to the foregoing phenols.

VI. Grignard reagents of the formula RMgX wherein R is an organic radical which forms a Grignard reagent and X is halogen, e.g,. R may be alkyl, cycloalkyl, aryl,

substituted alkyl, substituted cycloalkyl or substituted EXAMPLE 1 l-(Morpholinoimidocarbonyl)-2-( 1H )-pyridone Morpholine, 0.202 ml, is added to a stirred solution of 280 mg of 2-oxo-l-(2H)-pyridinecarbonitrile in 30 ml of ether and the solution is stirred at roomtemperature under atmospheric pressure for one hour. The sol- Examgle Column I column 11 O N-H Ci ll 2 piperidine N-C-Q N-H 3 pyrrolidine N- 0- Ni] IN-H 4 thiophenol E,, l

0 111- Na r 5 sodium phenoxide -yc0 N-H 6 aniline l l 7 n-pentylamine v- C -N-CH (CH CH v vent is then removed at reduced pressure and the residue is purified by preparative thin-layer chromatography on silica gel, using ethanol as the developing solvent. A uv absorbing band, having an R, of 0. l 6 to 0.6l is collected and washed from the silica gel with methanol. The solvent is removed in vacuo giving 82 mg of crystalline solid that, after several recrystallizations from ethyl acetate, melts at l171l8. The nmr and ir spectra indicate that the product has the following structure:

Anal. calcd for C H N O z C, 57.96; H, 6.32; N, 20.28. Found: C, 57.83; H, 6.29; N, 20.23.

EXAMPLES 2-17 Following the procedure of Example 1 but substituting for morpholine an equivalent amount of the nucleophile indicated in Column I, there is obtained the compound of Column II.

I fi -MgBr 8 phenyl magnesium bromide 64 C Column II Column I Exam 1e sodium thiophenolate l0 n-butylmercaptan ll diethylamine l2 diphenylamine 13 sodium ethoxide sodium dielhylmalonate 15 Mg (c n 2 l7 TIOC H Examgle Column 1 21 Mg (C 11 2 22 NEANH EXAMPLES 23-24 Treatment of the product of Examples 5, 8, 9 and l422 with one equivalent of hydrochloric acid results in replacing with hydrogen the Na of Examples 5, 9, 14, 20 and 22, the MgBr of Example 8, the Mg of Examples and 21, the Ca of Example 16, the T1 of Example 17, the Cd of Example 18, and the Li of Example 19.

We claim:

1. A compound of the formula wherein O is alkyl, alkoxy, alkylthio, monoor dicyclic carbocyclic aryl, monoor dicyclic carbocyclic aryloxy, monoor dicyclic carbocyclic arylthio, amino, monoalkylamino, dialkylamino, m0no(monoor dicyclic carbocyclic aryl)amino, di(monoor dicyclic carbocy- Column II with a nucleophilic compound of the formula QM,

wherein Q and M are as defined in claim 6. 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 having the name 1-(morpholinoimidocarbonyl)-2-(1H)-pyridone.
 3. A method for preparing a compound according to claim 1 which comprises the step of reacting a compound of the formula 